This invention relates to novel chroman compounds, pharmaceutical compositions containing such compounds, and methods of treating beta-3 adrenoreceptor-mediated conditions with such compositions.
Adrenoreceptors, or adrenergic receptors, are sites on effector organs that are innervated by postganglionic adrenergic fibers of the sympathetic nervous system, and are classified as either alpha-adrenergic or beta-adrenergic receptors. Alpha-adrenergic receptors respond to norepinephrine and to such blocking agents as phenoxybenzamine and phentolamine, whereas beta-adrenergic receptors respond to epinephrine and to such blocking agents as propranolol.
Beta-adrenergic receptors are sub-classified as beta-1, beta-2, and beta-3 adrenoreceptors. Generally, beta-1 stimulation causes cardiostimulation, whereas beta-2 stimulation causes bronchodilation and vasodilation.
Beta-3 receptors are found on the cell surface of both white and brown adipocytes where their stimulation promotes both lipolysis and energy expenditure. Agonists of beta-3 adrenoreceptors are known to be useful in the treatment of hyperglycemia (diabetes) and obesity in mammals, as well as in the treatment of gastrointestinal disorders and neurogenetic inflammation (U.S. Pat. No. 5,561,142). Additionally, they are known to lower triglyceride and cholesterol levels and to raise high-density lipoprotein levels in mammals (U.S. Pat. No. 5,451,677). Accordingly, they are useful in the treatment of conditions such as hypertriglyceridaemia, hypercholesterolaemia and in lowering high-density lipoprotein levels as well as in the treatment of atherosclerotic and cardiovascular diseases and related conditions. In addition, beta-3 adrenoreceptor agonists may also be useful in treating patients with impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes.
Additionally, it is also believed that the compounds of this invention are effective in the treatment of ocular hypertension and glaucoma, and in the treatment of urological disorders including benign prostatic hyperplasia and incontinence, as well as in the treatment of prostate disease and as topical anti-inflammatory agents.
It has now been found that certain novel chroman derivatives are effective as beta-3 agonists and are useful in the treatment of beta-3 mediated conditions.
This invention relates to chroman compounds of Formula I wherein, 
R is hydroxy, oxo, halo, cyano, nitro, C1-C10 alkyl optionally substituted with phenyl, C1-C10 haloalkyl, CF3, NR1R1, SR1, OR1, SO2R2, OCOR2, NR1COR2, COR2, NR1SO2R2, phenyl, or a 5- or 6-membered heterocycle with 1 to 4 heteroatoms selected independently from O, S, and N, each cyclic moiety being optionally substituted with hydroxy, R1, halo, cyano, NR1R1, SR1, CF3, OR1, C3-C8 cycloalkyl, NR1COR2, COR2, SO2R2, OCOR2, NR1SO2R2, C1-C10 alkyl, or C1-C10 alkoxy;
R1 is hydrogen, (CH2)dxe2x80x94Oxe2x80x94(CH2)dR5, where each d is selected independently, or C1-C10 alkyl optionally substituted with 1 to 4 substituents each independently selected from hydroxy, halo, CO2C1-C4 alkyl, CO2H, S(O)bC1-C10 alkyl, C1-C10 alkoxy, and phenyl optionally substituted with CO2C1-C4 alkyl or CO2H, or C3-C8 cycloalkyl, phenyl, or naphthyl, each optionally substituted with 1 to 4 substituents each independently selected from halo, nitro, oxo, C1-C10 alkyl, C1-C10 alkoxy, and C1-C10 alkylthio; and
when two R1 groups are attached to N as NR1R1, these R1 groups may form together with the nitrogen to which they are attached, a heterocyclic ring containing 4 to 7 C atoms, 1 to 2 N atoms, and 0 to 1 O or S atoms;
R2 is R1; OR1; NR1R1; NHS(O)bphenyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halo, or nitro; NHS(O)bnaphthyl; NHS(O)bC1-C10 alkyl; or a 5- or 6-membered heterocycle with one or more heteroatoms selected independently from O, S, and N, said heterocyclic moiety being optionally substituted with R1;
R3 is hydrogen, C1-C10 alkyl, benzyl, or COR2;
R4 is hydrogen, C1-C10 alkyl, C1-C10 alkyl-phenyl, C1-C10 alkyl-pyridine;
R5 is hydrogen or COOH;
Ar is phenyl optionally fused to a cyclohexyl, phenyl, or a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from O, S, and N, said bicyclic moiety being optionally fused to phenyl, or a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, optionally fused to phenyl;
X is O or S(O)b;
Y is halo, R1, OR1SR1, CO2R1, NR1R1, S(O)b-phenyl-CO2R1, or phenyl optionally fused to another phenyl ring or to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, or a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, optionally fused to a phenyl ring, each cyclic moiety being optionally substituted with one or more substituents independently selected from COR2; halo; OR1; NR1R1; R1; C1-C10COR2; phenyl optionally substituted with halo, C1-C4 alkyl, or C1C4 alkoxy; tetrazolo; or 
xe2x80x83where, when the two R4 groups attached to the same C are both alkyl, they optionally may be joined so that, when taken together with the C to which they are attached, they form a spiro ring of 3, 5, or 6 C atoms, or where the R4 attached to N and one R4 attached to the adjacent C are both alkyl, they optionally may be joined so that, taken together with the atoms to which they are attached, they form a 5- or 6-membered heterocycle;
a is 0, 1, 2, 3, 4, or 5;
b is 0, 1, or 2;
d is 1, 2, or 3;
e is 1 or 2;
and pharmaceutically acceptable salts and esters thereof.
The terms identified above have the following meaning throughout:
C1-C10 alkyl means straight or branched chain alkyl groups having from one to about ten carbon atoms, which may be saturated, unsaturated, or partially saturated. Such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, as well as vinyl, allyl, propynyl, butenyl, butadienyl, isopropenyl, methyleneyl, ethylenyl, propenyl, ethynyl, and the like.
C1-C10 haloalkyl means straight or branched chain alkyl groups having from one to about ten carbon atoms where any Cxe2x80x94C bond may be saturated or unsaturated, the alkyl groups being substituted at any available carbon atom with one or more halogen atoms, and includes such groups as trifluoromethyl, trichloromethyl, pentafluoroethyl, fluoromethyl, 6-chlorohexyl, and the like.
The term C1-C10 alkoxy means straight or branched chain alkoxy groups having from one to about ten carbon atoms where any Cxe2x80x94C bond may be saturated or unsaturated, and includes such groups as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
The term C1-C10 alkylthio means straight or branched chain alkylthio groups having from one to about ten carbon atoms where any Cxe2x80x94C bond may be saturated or unsaturated, and includes such groups as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like.
C3-C8 cycloalkyl means saturated mono cyclic alkyl groups of from 3 to about 8 carbon atoms, and includes such groups as cyclopropyl, cyclopentyl, cyclohexyl, and the like.
Halo includes fluoro, chloro, bromo, and iodo, unless specifically stated otherwise.
R2, Ar and Y each includes any 5- or 6-membered saturated or unsaturated heterocyclic group having any combination of one or more N, S, or O atoms, with the point of attachment being at any available position on the heterocyclic ring. Where there is more than one heteroatom in a single cyclic group, each heteroatom shall be chosen independently of any other heteroatom, in each occurrence. These moieties include such 5-membered heterocylic groups as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrahydrofuryl, dihydrofuryl, pyrrolidinyl, pyrrolinyl, dihydrothienyl, tetrahydrothienyl, dioxolyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, triazolyl, triazolinyl, triazolidinyl, oxadiazolyl, thiadiazolyl, furazanyl, tetrazolyl and the like. It also includes such 6-membered heterocyclic rings such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, dihydropyranyl, thiopyranyl, triazinyl, dioxanyl, piperidinyl, piperazinyl, pyrazinyl, morpholinyl, and the like.
Ar and Y also each includes phenyl fused to any 5- or 6-membered heterocyclic ring described above to form a bicyclic moiety, which may be saturated or unsaturated and may have any combination of one or more N, S, or O atoms, with the point of attachment being at any available position on the phenyl ring. These include such phenyl fused 5-membered heterocyclic groups as benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indazolyl, indolinyl, indazolinyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzothiazolinyl, benzimidazolyl, benzimidazolinyl, benzisoxazolyl, benzisoxazolinyl, benzothiadiazolinyl, benzisothiazolyl, benzisothiazolinyl, benzotriazolyl, benzoxadiazolyl, benzoxadiazolinyl, benzothiadiazolyl, benzopyrazolinyl, and the like. It also includes such phenyl fused 6-membered heterocyclic groups as quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, chromenyl, phthalazinyl, dihydrobenzopyranyl, benzothiopyranyl, dihydrobenzothiopyranyl, benzoxazinyl, benzodioxanyl, benzodioxenyl, and the like.
Ar also includes phenyl fused to any 5- or 6-membered heterocyclic ring to form a bicyclic moiety as described above, which is further fused on the heterocyclic ring to a second phenyl ring, forming a tricyclic system, with the point of attachment to the core structure of the compound of Formula I being at any available position of the first phenyl ring. These include such groups as carbazolyl, carbazolinyl, acridinyl, xanthenyl, phenoxathiinyl, phenoxazinyl, phenanthridinyl, dibenzofuryl, dibenzopyranyl, dibenzodioxanoyl, phenazinyl, thianthrenyl, and the like.
Ar also includes any 5- or 6-membered saturated or unsaturated heterocyclic ring having any combination of one or more N, S, or O atoms, which is further fused to a phenyl ring, with the point of attachment to the core molecule of Formula I being at any available position on the heterocyclic ring. These include phenyl-fused with 5-membered hetero-bicyclic moieties such as benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indazolyl, indolizinyl, indolinyl, indazolinyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzothiazolinyl, benzimidazolyl, benzimidazolinyl, benzisoxazolyl, benzisoxazolinyl, benzisothiazolyl, benzoisothiazolinyl, benzopyrazolinyl, and the like. It also includes phenyl-fused with 6-membered hetero-bicyclic groups such as quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, chromenyl, phthalazinyl, dihydrobenzopyranyl, benzothiopyranyl, dihydrobenzothiopyranyl, benzoxazinyl, benzodioxanyl, benzodioxenyl, and the like.
C1-C10-alkyl-phenyl means straight or branched chain saturated alkyl groups having from one to about ten carbon atoms where the phenyl moiety is attached at any available position on the alkyl group. Examples of these moieties include benzyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-methyl-2-phenylethyl, 5-phenylpentyl, 4-phenylhexyl and the like.
C1-C10-alkyl-pyridyl means straight or branched chain saturated alkyl groups having from one to about ten carbon atoms where the pyridyl moiety is attached at any available position on the alkyl group. The pyridyl group may be attached to the alkyl group from any available position on the pyridine ring. Examples of these include pyridyl, 2-(2-pyridyl)ethyl, 3-(4-pyridyl)-propyl, 2-(3-pyridyl)-propyl, 1-methyl-2-(3-pyridyl)-ethyl, 5-(3-pyridyl)-pentyl, 4-(4-pyridyl)-hexyl, and the like.
S(O)b-phenyl-CO2R1 means a phenylthio, a phenylsulfinyl or a phenylsulfonyl group, attached at any available position on the phenyl ring to a CO2R1 moiety.
When any moiety is described as being substituted, it may have one or more of the indicated substituents that may be located at any available position on the moiety. When there are two or more substituents on any moiety, each term shall be defined independently of any other in each occurrence. For example, NR1R1 may represent NH2, NHCH3, N(CH3)CH2CH2CH3, and the like; or for example, Ar(R)a, where a=3, Ar may be substituted by three (3) different substituents such as hydroxy, halo, and alkyl, and the like.
Illustrative examples of the compounds of Formula I in this invention include but are not limited to those summarized in Table 1 below:
As is true of most classes of therapeutically effective compounds, certain subclasses and certain species which are particularly effective are preferred over others. For example, one preferred set of compounds of Formula I are those wherein X is O or S; and Y is R1, phenyl or a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, each cyclic moiety being optionally substituted with one or more substituents selected from COR2, halo, or C1-C10 alkyl.
A more preferred set of compounds of Formula I are those wherein a is 0, 1, or 2; Ar is phenyl, a 5- or 6-membered heterocycle containing one heteroatom, phenyl fused to a 5- or 6-membered heterocycle, or carbanzolyl or carbanzolinyl; X is O; R3 is hydrogen; d is 1; Y is phenyl substituted with COR2; and R2 is OR1.
Representative salts of the compounds of Formula I include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate.
Base salts include, for example, alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromides and others.
The esters in the present invention are non-toxic, pharmaceutically acceptable esters such as alkyl esters, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl esters. Additional esters such as phenyl-C1-C5 alkyl may be used, although methyl ester is preferred. The compound of Formula I may be esterified by a variety of conventional procedures including reacting the appropriate anhydride, carboxylic acid, or acid chloride with the alcohol group of the Formula I compound. The appropriate anhydride is reacted with the alcohol in the presence of an acylation catalyst such as 1,8-bis[dimethylamino]naphthalene or N,N-dimethylaminopyridine. An appropriate carboxylic acid can be reacted with the alcohol in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide or other water soluble dehydrating agents which are used to drive the reaction by the removal of water and, optionally, an acylation catalyst. Esterification can also be reached using the appropriate carboxylic acid in the presence of trifluoroacetic anhydride and, optionally, pyridine, or in the presence of N,N-carbonyldiimidazole with pyridine. Reaction of an acid chloride with the alcohol is carried out with an acylation catalyst such as 4-DMAP or pyridine.
Sensitive or reactive groups on the compound of Formula I may need to be protected during any of the above methods for forming esters, and protecting groups may be added and removed by conventional methods well known in the art.
One skilled in the art would readily know how to successfully carry out these as well as other methods of esterification of alcohols.
The compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers. Any isomer may be present in the (R)-, (S)-, or (R,S) configuration, preferably in the (R)- or (S)- configuration, whichever is most active. The configurational isomers of Formula I, in which both
1. the hydroxyl group attached to the side chain containing the Arxe2x80x94Xxe2x80x94 moiety and
2. the (CH2)d group attached to the dihydrochromenyl ring
are above the plane as depicted below 
are preferred.
All isomers of the compounds of this invention, whether separated, pure, partially pure, or in a diastereomeric or racemic mixture, are encompassed within the scope of this invention. The purification of said isomers and the separation of said isomeric mixtures can be accomplished by standard techniques known in the art.
Geometric isomers by nature of substituents about a double bond or a ring may be present in cis (xe2x95x90Zxe2x80x94) or trans (xe2x95x90Exe2x80x94) form, and are each encompassed within the scope of this invention.
The particular process to be utilized in the preparation of the compounds of this invention depends upon the specific compound desired. Such factors as the selection of the specific Ar, X, and Y moieties, and the specific substituents on the various moieties, all play a role in the path to be followed in the preparation of the specific compounds of this invention. These factors are readily recognized by one of ordinary skill in the art.
For synthesis of any particular compound, one skilled in the art will recognize that the use of protecting groups may be required for the synthesis of compounds containing certain substituents. A description of suitable protecting groups and appropriate methods of removing such groups may be found in: Protective Groups in Organic Synthesis, Second Edition, T. W. Greene, John Wiley and Sons, New York, 1991. For example, after preparation of a compound according to Reaction Scheme 1, in order to enable purification of the end product by, for instance, flash chromatography, compounds of Formula I wherein R3 is H, can be selectively protected, for example, as a carbamate derivative obtained by, for example, treatment with a reagent such as di-tert-butyl dicarbonate or other means known in the art. After purification, the carbamate group can easily be removed by treatment with an acid such as HCI or trifluoroacetic acid by methods known in the art.
In the Reaction Schemes below, one skilled in the art will recognize that reagents and solvents actually used may be selected from several reagents and solvents well known in the art to be effective equivalents. When specific reagents or solvents are shown in a Reaction Scheme, therefore, they are meant to be illustrative examples of specific but not limiting conditions for the execution of that particular Reaction Scheme.
General Methods of Preparation of Formula I Compounds
In general, Formula I compounds may be prepared by standard techniques known in the art and by known processes analogous thereto. In particular, three such standard methods may be used, the selection of which may be based, among other considerations, upon the commercial availability of the required individual starting materials. These three methods are illustrated in Reaction Schemes 1, 2, and 3 below.
The compounds of Formula I where each variable may be any moiety within that variable""s definition may be synthesized according to Reaction Scheme 1 by coupling an appropriate epoxide 1 with an appropriate amine 2 where R3 is hydrogen or alkyl. The epoxide 1 is either commercially available, known in the art, or for Formula I compounds where X is O or S, may be readily prepared from known hydroxy or thiol compounds as exemplified in Reaction Scheme 10. Formula I compounds in which X is SO or S(O)2 may be generally prepared from other Formula I compounds where X is S by oxidation with reagents such as Oxone(copyright) or mCPBA. Preparation of 2 is described in Reaction Schemes 15, 16, 17, 20, 21, and 22 below. The reaction of Reaction Scheme 1 is typically carried out in an aprotic solvent such as dimethyl sulfoxide, dimethyl formamide, acetonitrile, or in an alcohol such as ethanol, isopropanol, or propanol at a temperature of from about xe2x88x9210xc2x0 C. to reflux. Compounds in which R3 is other than hydrogen may be prepared by reaction of compound I in which R3 is H, by selective N-alkylation or N-acylation reactions with known compounds of formula R3-halo (where R3 is alkyl, benzyl, or acyl; or [R3]2O where R3 is acyl). Protection of the hydroxyl group, for example as a Cbz ester, may be required prior to N-alkylation reactions; O-deprotection is carried out under standard conditions well known in the art. 
Alternatively, Formula I compounds, where each variable may be any moiety within that particular variable definition except that d=1 may be prepared by a reductive amination as shown in Reaction Scheme 2, involving reaction of an aldehyde of Formula 4 (preparation described below in Reaction Scheme 11) with an amino alcohol of Formula 3 (preparation described below in Reaction Scheme 10). Compounds in which R3 is other than hydrogen may be prepared by reaction of compound Ia in which R3 is H, by selective N-alkylation or N-acylation reactions with known compounds of formula R3-halo (where R3 is alkyl, benzyl, or acyl; or [R3]2O where R3 is acyl). Protection of the hydroxyl group, for example as a Cbz ester, may be required prior to N-alkylation reactions; O-deprotection is carried out under standard conditions well known in the art. 
A third general route to Formula I compounds, where each variable may be any moiety within that particular variable definition except that d=1 is shown in Reaction Scheme 3, in which an amino alcohol 3 and a carboxylic acid 5 (preparation described in Reaction Schemes 12 and 13) are coupled to provide an amide of Formula 6. Reduction of the Formula 6 amides with an appropriate reagent such as borane-dimethylsulfide complex provides the Formula I compounds where R3 is H. Formula I compounds in which R3 is other than H may be similarly prepared as described above for Reaction Schemes 1 and 2.
Compounds of Formula I or Formula Ia where Y is any alkyl, cycloalkyl, phenyl or a 5-or 6-membered heterocyclic ring, may be prepared from compounds of Formula I or Formula Ia where Y is a halogen, using the methods described below. For example, a compound of Formula I, wherein Y is iodo, may be prepared by Reaction Scheme 1 using corresponding starting materials 2 or 4, where Y is iodo, each of which may be prepared by Reaction Schemes 14 or 12, respectively. The resulting Formula I compound is then protected by standard methods to give a compound of Formula II, as shown in Reaction Scheme 4. The compound of Formula II is then converted to the boronic ester III, which is then subjected to Suzuki coupling reactions with a Y-halo or Yxe2x80x94OSO2CF3 compound, in which Y is any alkyl, cycloalkyl, xe2x80x94(CH2)dxe2x80x94Oxe2x80x94(CH2)dR5, phenyl, naphthyl, or a 5- or 6-membered heterocycle, to provide Formula IV compounds. Deprotection of Formula IV compounds by acid or fluoride-catalyzed hydrolysis provides the corresponding Formula I compounds. 
The coupling may also be performed in the reverse manner, that is, a boronic acid or boronic ester derivative 14, prepared from a halophenyl or phenyltriflate compound 13a, may be added to the halo compound of Formula IIa, as shown in Reaction Scheme 5, to give Formula Id compounds. 
Formula 1 compounds wherein Y is CO2R1 or 
where R1 and R4 are as described above, may be prepared, for example, by a sequence shown in Reaction Scheme 6. The iodo compound of Formula II may be converted to the carboxylic acid of Formula IIb by palladium-catalyzed carboxylation which may then be coupled with any amino acid using standard peptide synthesis techniques, deprotected and hydrolyzed to give compounds of Formula If. This method may be repeated to give Formula I compounds where Y is 
by an analogous sequence of reactions performed on the Formula If compounds. 
Other Formula I compounds wherein Y is NR1R1 or a nitrogen heterocycle may be prepared from the nitro compound of Formula Im by reduction to Ig followed by alkylation to Ih (Reaction Scheme 7). Formula Im compounds may be prepared according to Reaction Scheme 1 or 3, starting from the known Formula 5 or Formula 2 compounds in which Yxe2x95x90NO2. 
Other Formula I compounds in which Y is xe2x80x94S(O)bPhxe2x80x94CO2R1, X is O or S(O)2, and b is 0 may be prepared by reduction followed by diazotization and nucleophilic displacement of the diazonium intermediate with an arylthiol to give arylthioethers of Formula Ii (Reaction Scheme 8). Oxidation of the Formula Ii compound with mCPBA or Oxone(copyright) generates the Formula Ij compound in which Y is xe2x80x94S(O)bPhxe2x80x94CO2R1 and b=1 or Formula Ik compound in which Y is xe2x80x94S(O)bPhxe2x80x94CO2R1 and b=2, depending on the number of equivalents of oxidant used in the reaction.
Formula I compounds in which Y is SR1 or OR1 may be similarly prepared by methods analogous to Reaction Scheme 8, by substituting HSR1 or HOR1 in place of the arylthiol. 
Formula I compounds where X is SO or S(O)2 may be prepared by oxidation of Formula I compounds where X is S by using reagents well known in the art for such oxidation such as Oxone(copyright) and mCPBA.
Formula I compounds, in which Y is phenyl substituted by a PhSO2NHxe2x80x94 or alkylSO2NHxe2x80x94 group, may be prepared from the corresponding carboxylic acids as shown in Reaction Scheme 9. An example of dehydrating/acylation conditions useful in this scheme is a mixture of 1-3-dimethylaminopropyl-3-ethylcarbociimide (EDCl) and 4-dimethylaminopyridine (DMAP) in an inert solvent such as dichloromethane. 
Other compounds of Formula I may be prepared by standard methods starting from other Formula I compounds, by interchanging the functional groups attached to the Y moiety. Reactions useful for carrying out such interchanges include, but are not limited to esterification, saponification, oxidation, reduction, O- and N-alkylation, acylation, aromatic nucleophilic substitution, and Suzuki coupling reactions. Procedures to carry out such reactions are well nown to those in the art.
The salts and esters of the Formula I compounds of the invention may be readily prepared by conventional chemical processes well known in the art.
General Method of Preparation of Intermediates
The starting materials required to carry out the above described reactions (e.g., epoxides 1, amines 2, amino alcohols 3, aldehydes 4, and carboxylic acids 5) are in many cases commercially available or may be readily prepared by methods known to those skilled in the art. The following routes are exemplary of such methods, but are not intended to be limiting in any way.
The epoxides 1 of Reaction Scheme 1 are commercially available or may be prepared according to one of the many procedures described in the literature known to those skilled in the art, from starting materials which are themselves either commercially available or known in the art. One such general method of preparation is illustrated in Reaction Scheme 10, in which a substituted aryl or heteroaryl hydroxy or thiol compound (i.e., where X is S or O), such as a phenol, thiophenol, hydroxypyridine, hydroxybenzofuran, thiopyridine, hydroxyindole, hydroxyquinoline, thioquinoline and the like is allowed to react with a glycidyl-, alkyl- or arylsulfonate in the presence of a strong base such as sodium hydride. The alkyl or aryl sulfonate used in this reaction may be racemic or an enantiomerically pure compound, such as (2S)-(+)- or (2R)-(xe2x88x92)-glycidyl tosylate, both of which are commercially available. 
The amino alcohols 3 are either commercially available, known in the art, or may be prepared by ring opening of the epoxides 1 with a nitrogen nucleophile, such as dibenzylamine or phthalimide, in the presence of a base. Removal of the phthalimide by cleavage with hydrazine or the benzyl groups by hydrogenolysis provides the desired amino alcohol of Formula 3. An example of this is shown in Reaction Scheme 11.
Synthesis of aldehyde starting materials of Formula 4 may be accomplished from the carboxylic acids of Formula 5 by reduction with borane followed by an oxidation, for example, under Swern conditions as shown in Reaction Scheme 12. This method is compatible with a wide variety of Y groups, although in some cases a protection group may also be employed and removed in a subsequent step. 
The carboxylic acids of Formula 5 are generally available from the known unsubstituted chroman carboxylic acid, 5a (WO 99/32476), by various aromatic substitution reactions at the 6-position of the chroman ring and further elaboration of these products. For example, halogenation, e.g., iodination of 5a gives the 6-iodo compound 5b and nitration gives predominantly the 6-nitro analog, 5c (U.S. Pat. No. 6,051,586) as shown in Reaction Scheme 13.
Conversion of 5b or 5c to other carboxylic acids of general Formula 5 where Y is xe2x80x94(CH2)nCOR2 and n is 0, 1 or 2 has been described in the art (U.S. Pat. No. 6,051,586). Other compounds of Formula 5 where Y is any alkyl, cycloalkyl, xe2x80x94(CH2)dxe2x80x94Oxe2x80x94(CH2)dR5, phenyl, naphthyl, or a 5- or 6-membered heterocycle, may be prepared by Suzuki coupling of a halo-Y group to a iodo chroman ester, prepared by standard esterification methods from the iodo chroman acid 5b. 
The amine starting materials of Formula 2 in which d=1 are generally available by standard methods involving conversion of a carboxylic acid 5 to an amide of Formula 11 and reduction with borane, or further conversion of the Formula 11 amide to the nitrile of Formula 12 and reduction by hydrogenation. This sequence is shown in Reaction Scheme 15 for Formula 2 amines wherein d=1 and R3 is H. Formula 2 amines in which R3 is other than H may be prepared by the standard alkylation or acylation methods known in the art, as described above. 
Formula 2 amines in which d is 2 or 3 may be prepared by standard homologation sequences of known intermediates where d=1. For example, aldehydes of Formula 4 can undergo an alkyl chain extension according to well known procedures such as that described by Wittig, G. et al., in Chem. Ber., 1962, 2514, and the process may be repeated in order to prepare the acetic and propionic acid homologues of Formula 5. These chain-extended acids may used in place of the acid of Formula 5 by a method analogous to Reaction Scheme 15, to provide a variety of Formula 2 amines in which d=2 or 3.
Formula 2 amines in which Y is other than hydrogen or halo may be prepared by palladium-catalyzed coupling reactions on the N-protected amine of Formula 15a, followed by deprotection, as shown in Reaction Scheme 16. Formula 2 amines prepared in this way in which the Y group is substituted by an acid, ester, alcohol, ketone, sulfide, or nitro group can also provide additional Formula 2 amines by manipulation of that functional group by directed hydrolysis, esterification, reduction, oxidation, and/or reduction reactions and the like. 
Similarly, the unsubstituted amine 2c, after protection may be directly substituted at the 6-position of the chroman under Friedel-Crafts alkylation or acylation conditions to provide compounds of Formula 15b in which Y is any alkyl, cycloalkyl, or CO2R1 group. An example of this where Y is an optionally substituted alkanoic acid group is shown in Reaction Scheme 17.
Alcohol intermediates of Formula 9 in which Y is other than hydrogen or halo may also be prepared from the iodo alcohol, 9a, by the previously described Suzuki coupling methodology as shown in Reaction Scheme 18. This may be accomplished either directly on 9a, or via a 4-step sequence involving protection of the alcohol to 16a, for example as the t-butyltrimethylsilyl ether, conversion of the halide to the boronic ester, Suzuki coupling to 16b, and finally deprotection to 9.
The halo-Y compounds used in Reaction Schemes 14, 16, and 18 where halo is iodo, chloro, or bromo, and Y is any alkyl, cycloalkyl, xe2x80x94(CH2)dxe2x80x94Oxe2x80x94(CH2)dR5, phenyl, naphthyl, or a 5- or 6-membered heterocycle, are either commercially available or synthesized by standard methods known to those skilled in the art. One such standard method is direct halogenation of a known Hxe2x80x94Y compound with a halogenating agent; other methods include the functional group conversion of HOxe2x80x94Y, NH2xe2x80x94Y compounds to halo-Y compounds by standard substitution methods. Y-halo compounds containing a fluoro substituent may be converted to Y-halo compounds containing alkylamino moiety by nucleophilic aromatic substitution catalyzed by cesium carbonate.
An illustration of the preparation of halo of halo-Y compounds of Formula 13a and 13b, where Y represents an oxazole or a thiazole, prepared by direct halogenation of the unsubstituted compound 17, or by diazotization of a NH2xe2x80x94Y compound 18 as shown in Reaction Scheme 19.
The heterocyclic intermediates, 17, and 18, used to prepare 13a and 13b are accessible by standard methods from acyclic materials, for example, as shown in Reaction Schemes 20, 21, and 22.
Using a combination of the above Reaction Schemes, a wide variety of compounds of Formula I may be prepared. Further illustration of these methods are in the specific Examples described hereinbelow. These examples are not intended nor should they be construed to limit the invention in any way.
General Experimental Procedures
HPLC-electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a YMC Pro C18 2.0 mmxc3x9723 mm column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Gradient elution from 90% A to 95% B over 4 minutes was used on the HPLC. Buffer A was 98% water, 2% acetonitrile, and 0.02% TFA. Buffer B was 98% acetonitrile, 2% water, and 0.018% TFA. Spectra were scanned from 140-1200 amu using a variable ion time according to the number of ions in the source.
Combinatorial/parallel reactions were carried out in 8-mL glass vials with Teflon-lined screw caps, or in a polypropylene reaction block consisting of an 8xc3x9712 matrix of ninety-six 2.0-mL reaction wells, with each reaction well incorporating a 15-45 micron polyethylene frit; reaction blocks of this type are commercially available as FlexChem(trademark) reactor blocks from Robbins Scientific Corporation, Sunnyvale, Calif. The reactor blocks are sealed with rubber gaskets and a clamping device, and can be heated with mixing by rotation in an oven (Robbins Scientific). LC/MS analyses were carried out with electrospray ionization, by using a YMC Pro C18 3 xcexcm column, 4.0 mmxc3x9723 mm, at 1.5 mL/min, with 0.5 min at 90% solvent A, then gradient elution at 0.5 to 4.0 min from 90% A to 5% A, then 0.5 min at 5% solvent A. Solvent A was 98% water and 2% acetonitrile, containing 0.02% trifluoroacetic acid; solvent B was 98% acetonitrile and 2% water, containing 0.02% trifluoroacetic acid.
The following examples are presented to illustrate the invention described herein, but should not be construed as limiting the scope of the invention in any way.